thromboxane-a2 and Arterial-Occlusive-Diseases

Topics: Arterial Occlusive Diseases; Blood Coagulation Factors; Blood Platelets; Comorbidity; Endothelium, Vascular; Fibrinolysis; Free Radicals; Genetic Predisposition to Disease; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Nitric Oxide; Oxidative Stress; Thrombin; Thrombomodulin; Thrombophilia; Thromboxane A2

Topics: Arterial Occlusive Diseases; Aspirin; Fish Oils; Humans; Platelet Aggregation Inhibitors; Prostaglandin Antagonists; Thromboxane A2

To investigate the mechanisms responsible for the accelerated radioaerosol transalveolar clearance rates caused by acute balloon occlusion of the pulmonary arterial tree in dogs, the effects of vagal tone (n = 5) and prostaglandins (n = 21) including thromboxane were evaluated. In 15 animals, serial pulmonary arterial and aortic blood samples were acquired to evaluate pertinent metabolic products. Balloon occlusion of a localized arterial territory caused significant acceleration of technetium-99m diethylenetriamine pentaacetic acid (Tc-99m DTPA) clearance in the zone immediately distal to the occlusion (baseline clearance half-time 23.1 +/- 0/7 min versus 19.3 +/- 0.4 min, mean +/- SEM, p < 0.05). Vagotomy had no effect on occlusion-accelerated clearance. However, significant (p < 0.05) normalization did occur in the presence of indomethacin (21.9 +/- 0.4 min) and meclofenamic acid (20.4 +/- 0.5 min). Plasma values of thromboxane rose dramatically (pulmonary blood baseline 119 pg/ml to > 40,000 pg/ml) and transiently immediately after pulmonary vascular occlusion, and this rise was blunted significantly (peak pulmonary thromboxane B2 [TXB2] concentration = 668 pg/ml, p < 0.05) by meclofenamic acid. Significant normalization of local DTPA clearance rates also occurred in the presence of a thromboxane receptor blocker (n = 4), even when blood levels of thromboxane were elevated. Changes in transalveolar DTPA clearance rates after balloon occlusion of pulmonary arteries seem to a significant extent to be thromboxane-mediated.

Topics: Animals; Arterial Occlusive Diseases; Catheterization; Dogs; Meclofenamic Acid; Pulmonary Alveoli; Pulmonary Artery; Radiopharmaceuticals; Technetium Tc 99m Pentetate; Thromboxane A2; Thromboxane B2; Thromboxanes

Splanchnic artery occlusion shock was induced in male anaesthetized rats by clamping the splanchnic artery for 45 min. The arteries were then released and survival rate, mean survival time, mean arterial blood pressure, plasma levels of thromboxane B2 and 6-keto-PGF1 alpha, macrophage phagocytosis activity and plasma levels of myocardial depressant factor were evaluated. In addition, the neutrophilic infiltrate was quantified in the ileum and lung using a myeloperoxidase (MPO) assay. Sham splanchnic-artery-occlusion-shocked rats were used as controls. Splanchnic-artery-occlusion-shocked rats died within 93 +/- 7 min, while all sham-shocked animals survived more than 3 h. Splanchnic artery occlusion shock caused changes in mean arterial blood pressure, significantly increased the plasma levels of thromboxane B2 (7.5 +/- 1.3 ng/ml; p < 0.001 vs. sham), 6-keto-PGF1 alpha (8.9 +/- 1.7 ng/ml; p < 0.001 vs. sham) and myocardial depressant factor (114 +/- 11 U/ml), and reduced macrophage phagocytosis. Furthermore, MPO activity was significantly elevated (0.12 +/- 0.03 x 10(-3) and 1.8 +/- 0.5 x 10(-3) U/g protein in the ileum and lung, respectively) 70 min after starting reperfusion. Administration of BAY u3405, a novel thromboxane A2 receptor antagonist (30 mg/kg i.v., 30 min before occlusion), significantly increased survival time (187 +/- 3.7 min) and survival rate, improved mean arterial blood pressure, reduced the plasma levels of myocardial depressant factor (54 +/- 3 U/ml), partially restored macrophage phagocytosis and lowered MPO activity in both the ileum and the lung. Our data are consistent with an involvement of thromboxane A2 in splanchnic artery occlusion shock and suggest that BAY u3405 might be of benefit in low-flow states such as circulatory shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterial Occlusive Diseases; Blood Pressure; Carbazoles; Macrophages; Male; Myocardial Depressant Factor; Peroxidase; Phagocytosis; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Shock; Splanchnic Circulation; Sulfonamides; Survival Rate; Thromboxane A2; Thromboxane B2

Antithrombotic effects of KW-3635, a newly synthesized thromboxane (TX) A2-receptor antagonist, were studied in guinea pigs. In the extracorporeal circulation thrombosis model, the shunt was filled with thrombi, and reduction of platelet count and increase in plasma TXA2 concentration were observed. KW-3635 (30 and 100 mg/kg, p.o.) inhibited the thrombus formation in the shunt and prevented the decrease in platelet count in the circulating blood without affecting the red blood cell count. BM13,505 (30, 100 mg/kg, p.o.), another TXA2-receptor antagonist, and ticlopidine (300 mg/kg, p.o.), an antiplatelet drug, also inhibited the thrombus formation, while aspirin (10, 300 mg/kg, p.o.) did not. Peripheral arterial occlusive disease was induced by injection of sodium laurate into the femoral artery in guinea pigs. Daily oral administration of KW-3635 (3-30 mg/kg) significantly prevented the progression of vascular lesions. BM13,505 (3-30 mg/kg, p.o.) and ticlopidine (100 mg/kg, p.o.) also ameliorated the vascular lesions, whereas aspirin (10, 100 mg/kg, p.o.) did not. KW-3635 at concentrations up to 10(-4) M did not affect coagulation parameters in vitro. These results suggest that TXA2 is involved in the pathogenesis of arterial thrombotic and ischemic disorders. KW-3635 may be useful for the treatment of thrombotic disease and peripheral arterial occlusive diseases.

Topics: Animals; Arterial Occlusive Diseases; Aspirin; Benzimidazoles; Benzoxepins; Blood Coagulation; Blood Platelets; Disease Models, Animal; Erythrocyte Count; Femoral Artery; Guinea Pigs; Lauric Acids; Male; Phenylacetates; Platelet Count; Sulfonamides; Thrombosis; Thromboxane A2; Thromboxanes; Ticlopidine

We have developed a photochemical model to induce thrombotic occlusion of the guinea-pig femoral artery. Using this model, we investigated the effect of cholesterol feeding on arterial occlusion time in the guinea-pig. Animals were divided into two groups, one on standard diet and the other on standard diet containing 0.5% cholesterol for 3 weeks. The time for femoral artery occlusion was significantly shorter (p < 0.05) in cholesterol fed animals as compared to the control group. In vitro collagen-, U-46619- (a thromboxane A2 adenosine diphosphate analogue) and (ADP)-induced platelet aggregation responses in whole blood in cholesterol-fed animals were increased 13-, 10- and 4-fold, respectively. U-46619- and collagen-induced washed platelet aggregation responses were also significantly enhanced by cholesterol feeding (p < 0.01). Further, TXA2 generation by collagen-stimulated washed platelets in cholesterol-fed animals increased similar to the platelet aggregation responses. However, platelet-activating factor (PAF)-induced platelet aggregation in whole blood was relatively unaffected by cholesterol feeding. 11-dehydro TXB2 levels in plasma were increased significantly by cholesterol feeding. Our observations suggest that increased plasma TXA2 level and platelet aggregation response to TXA2 and stimulated TXA2 synthesis in platelets play a role in enhanced arterial occlusion in cholesterol fed guinea-pigs.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Animals; Arterial Occlusive Diseases; Cholesterol, Dietary; Collagen; Femoral Artery; Guinea Pigs; Male; Photochemistry; Platelet Activating Factor; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Thrombosis; Thromboxane A2; Time Factors

Platelets may accentuate vasoconstriction in stenotic arteries capable of vasomotion. We examined the interaction of platelets, stenosis, and arterial vasoconstriction in normal and stenotic arteries with intact endothelium. Beagle carotid arteries (n = 38) were isolated, removed, and placed in an in vitro perfusion system. Platelet-rich plasma (PRP) or platelet-poor plasma (PPP) were perfused through the arteries under constant pressure (100 mmHg) and a fixed distal resistance. In intact arteries without a stenosis, angiotensin II (ANG II) decreased luminal diameter without altering flow during PRP perfusion. After creating an intraluminal stenosis, vasoconstriction produced by ANG II resulted in near total cessation of flow. During PRP perfusion, this effect was amplified, demonstrating suppression of flow at significantly (P less than 0.05) lower concentrations of ANG II (PRP, ED50 = 0.03 +/- 0.01 x 10(-8) M) compared with arteries perfused with PPP (PPP, ED50 = 2.7 +/- 0.8 x 10(-8) M). This accentuated vasoconstrictor response in the presence of platelets was not blocked by SKF 96148 (a thromboxane A2 antagonist) but was abolished by ketanserin (a 5-HT2-serotonergic blocker). This increased sensitivity to vasoconstriction was not due to significant platelet plugging inasmuch as no cyclic flow reductions were observed, aspirin (acetylsalicylic acid) did not prevent this accentuated vasoconstrictor response, and adventitial administration of nitroglycerin restored flow to baseline levels. These studies illustrate that 1) platelets amplify the effect of vasoconstrictors in stenotic arteries, 2) this amplification of vasoconstriction is primarily due to platelet release of serotonin, and 3) the amplification occurs in the absence of significant platelet plugging and endothelial damage.

Topics: Animals; Arterial Occlusive Diseases; Blood Platelets; Carotid Arteries; Constriction, Pathologic; Dogs; Endothelium, Vascular; Microscopy, Electron, Scanning; Platelet Aggregation; Reference Values; Serotonin; Stress, Mechanical; Thromboxane A2; Vasoconstriction

The purpose of this study was to examine whether the blockade of thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptor by the selective TxA2/PGH2 receptor antagonist KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11- dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate, CAS 127166-41-0) is effective in enhancing tissue-type plasminogen activator (tPA)-induced thrombolysis and preventing reocclusion in a model of femoral artery thrombosis in anesthetized dogs. The thrombus was formed by inserting a copper coil into the femoral artery. Sodium heparin (100 U/kg i.v.) was administered shortly after the formation of thrombus. All dogs received i.v. tPA at a dose of 20 micrograms/kg/min starting 60 min after the formation of the occlusive thrombus for up to 60 min if necessary, to achieve reperfusion. After 30 min of thrombotic occlusion, the animals received vehicle (Group I, controls, n = 9) or KW-3635 (Group II, 0.3 mg/kg bolus i.v. + 0.3 mg/kg/h infusion, n = 9; Group III, 1 mg/kg bolus i.v. + 1 mg/kg/h infusion, n = 9) and the infusion of either vehicle or KW-3635 was continued thereafter throughout the experiment. The time to reperfusion in Group I was 37.3 +/- 5.2 min, while those in Group II and Group III were 25.3 +/- 6.2 min (p greater than 0.05) and 17.3 +/- 3.1 min (p less than 0.05), respectively. Reocclusion occurred within 4 h in 100% of Group I, whereas the incidence of reocclusion was reduced to 67% in Group II and to 0% in Group III. These data suggest that endogenous TxA2 generation is involved in lysis and rethrombosis during thrombolytic therapy by tPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arterial Occlusive Diseases; Benzimidazoles; Benzoxepins; Dogs; Female; Femoral Artery; Fibrinolytic Agents; Male; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Recurrence; Thrombosis; Thromboxane A2; Tissue Plasminogen Activator

Topics: Arterial Occlusive Diseases; Aspirin; Chronic Disease; Epoprostenol; Fatty Acids, Monounsaturated; Humans; Methacrylates; Polydeoxyribonucleotides; Pyridines; Thromboxane A2; Thromboxane-A Synthase

Contact between blood and foreign surfaces, e.g. vascular grafts, causes activation and release of platelets. One consequence of platelet activation is production of thromboxane A2 (TxA2). The physiological effects of TxA2, i.e. platelet aggregation and vaso-constriction are counteracted by another prostanoid, prostacyclin (PGI2). Acetylsalicylic acid (ASA) causes a longlasting inhibition of platelet TxA2 production and a more shortlasting inhibition of PGI2 production. The present study examines TxA2 and PGI2 synthesis in patients receiving synthetic arterial grafts, some of which were treated with ASA. The prostanoid synthesis was evaluated by measurement of their main urinary metabolites with gas chromatography-mass spectrometry. Platelet release was evaluated by measurements of beta-thromboglobulin (beta-TG) and the plasma coagulation by measurements of fibrinopeptide A (FPA). These compounds were also measured in urine in order to avoid artifacts caused by activation of platelets and plasma coagulation during blood sampling. Following replacement of the abdominal aorta with a synthetic vascular graft there was a marked increase in the synthesis of TxA2 and PGI2. Increased levels of beta-TG and FPA were also demonstrated. Administration of ASA on the first and second postoperative days significantly reduced the synthesis of TxA2 but caused no significant effects on the other parameters measured. It is concluded that ASA may be beneficial in the postoperative period since it counteracts TxA2 with vasoconstricting and platelet aggregating properties but leaves PGI2 with vasodilating and antiaggregating properties relatively uneffected.

Topics: Aged; Aorta, Abdominal; Aortic Aneurysm; Aortic Diseases; Arterial Occlusive Diseases; Aspirin; Blood Vessel Prosthesis; Epoprostenol; Female; Humans; Male; Thromboxane A2

We hypothesized that chronic ischemia of peripheral vascular disease would lead to increased thromboxane A2 (TxA2) and decreased prostacyclin (PGI2) production and surgical correction of the ischemia would stabilize TxA2 and PGI2 at normal levels. TxA2 and PGI2 concentrations were determined in 22 patients before, during, and after arterial reconstruction for limb salvage and in 10 control subjects. Control samples and preoperative patient samples had no detectable TxA2 or PGI2 (less than 26 pg/ml). Five minutes after reperfusion TxA2 increased (TxA2 = 76.27 +/- 48.9 pg/ml, mean +/- SEM) and persisted at 1 day (TxA2 = 190.1 +/- 80.1 pg/ml), 2 days (TxA2 = 224.7 +/- 131.7 pg/ml), 5 days (TxA2 = 334.8 +/- 272.8 pg/ml), and 7 days postoperatively (TxA2 = 256.6 +/- 149.0 pg/ml). Elevated TxA2 production was not associated with chronic ischemia of peripheral vascular disease. Reperfusion of the severely ischemic limb caused significant TxA2 release.

Topics: Adult; Arterial Occlusive Diseases; Epoprostenol; Female; Humans; Ischemia; Leg; Male; Thromboxane A2; Time Factors

The use of enzyme inhibitors to clarify the role of thromboxane A2 in vasoocclusive disease has been complicated by their non-specific action. To address this problem we have examined the effects of thromboxane A2/prostaglandin endoperoxide receptor antagonism in a canine model of platelet-dependent coronary occlusion. Two structurally distinct thromboxane A2/prostaglandin endoperoxide receptor antagonists, 3-carboxyl-dibenzo (b, f) thiepin-5,5-dioxide (L636,499) and (IS-(1 alpha,2 beta(5Z),3 beta,4 alpha))-7-(3-((2-((phenylamino)-carbonyl)hydrazino)methyl)-7- oxabicy-clo(2.2.1)-hept-2-yl)-5-heptenoic acid (SQ 29,548), were studied to ensure that the effects seen in vivo were mediated by receptor antagonism and did not reflect a nonspecific drug effect. Both compounds specifically inhibited platelet aggregation induced by arachidonic acid and by the prostaglandin endoperoxide analogue, U46619, in vitro and ex vivo, and increased the time to thrombotic vascular occlusion in vivo. When an antagonist (L636,499) was administered at the time of occlusion in vehicle-treated dogs, coronary blood flow was restored. In vitro L636,499 and a third antagonist, 13-azaprostanoic acid, specifically reversed endoperoxide-induced platelet aggregation and vascular smooth muscle contraction. Neither compound altered cyclic AMP in platelet-rich plasma before or during disaggregation. Therefore, reversal of coronary occlusion may reflect disaggregation of platelets and/or relaxation of vascular smooth muscle at the site of thrombus formation through specific antagonism of the thromboxane A2/prostaglandin endoperoxide receptor. Thromboxane A2/prostaglandin endoperoxide receptor antagonists are compounds with therapeutic potential which represent a novel approach to defining the importance of thromboxane A2 and/or endoperoxide formation in vivo.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arterial Occlusive Diseases; Bridged Bicyclo Compounds, Heterocyclic; Coronary Vessels; Dibenzothiepins; Dogs; Fatty Acids, Unsaturated; Hydrazines; Muscle Contraction; Muscle, Smooth, Vascular; Platelet Aggregation; Prostaglandin Endoperoxides; Prostanoic Acids; Rats; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

This study tested the hypothesis that aggregation of platelets and release of thromboxane A2 at the site of a coronary arterial stenosis may contribute to myocardial ischemia by impairing flow regulation of the distal coronary bed. Measurements of hemodynamics, flow (microspheres), lactate metabolism, and prostaglandin (PG) metabolites (thromboxane B2 and 6-keto-PGF1 alpha) were made in closed-chest anesthetized pigs instrumented with a stenosis (65% diam reduction) in the left anterior descending (LAD) coronary artery. Data were acquired prior to stenosis insertion (control) and 5 and 15 min after insertion, during which time thrombotic occlusion of the device was occurring. Heart rate was controlled by atrial pacing. Distal LAD zone endocardial flow (ml X min-1 X g-1) declined versus control (1.15 +/- 0.20, mean +/- SD) at 5 min (0.89 +/- 0.40, P less than 0.05) and 15 min (0.41 +/- 0.36, P less than 0.01) of occlusion. Distal endocardial resistance (mmHg X ml-1 X min X g), however, did not change versus control (72 +/- 12) at 5 (66 +/- 12) or 15 min (61 +/- 38). Distal epicardial resistance (mmHg X ml-1 X min X g) declined versus control (90 +/- 17) at 5 (66 +/- 35, P less than 0.05) and 15 min (43 +/- 26, P less than 0.01) postinsertion. Finally, lactate extraction (%) at control (42 +/- 19) changed to production 15 min postinsertion (-36 +/- 93, P less than 0.05) and arterial-anterior interventricular vein thromboxane B2 difference (pg/0.1 ml) changed from 13.1 +/- 17.8 pre to -15.8 +/- 30.0 at 5 min post (P less than 0.05). Thus platelet aggregation and release at a spontaneously thrombosing stenosis contribute to ischemia not only by reduction of stenosis diameter but also by impairment of flow regulation in endocardial layers distal to it.

Topics: Animals; Arterial Occlusive Diseases; Aspirin; Coronary Circulation; Heart Rate; Hemodynamics; Imidazoles; Lactates; Lactic Acid; Prostaglandin Endoperoxides, Synthetic; Regional Blood Flow; Swine; Thrombosis; Thromboxane A2; Vascular Resistance; Vasodilation

Topics: Arterial Occlusive Diseases; Ethanol; Humans; Platelet Aggregation; Thromboxane A2; Thromboxanes

Topics: Alprostadil; Angioplasty, Balloon; Anti-Bacterial Agents; Anticoagulants; Arterial Occlusive Diseases; Arteriosclerosis; Aspirin; Dipyridamole; Endarterectomy; Exercise Therapy; Fibrinolysis; Humans; Hyperlipidemias; Hypertension; Infusions, Intra-Arterial; Intermittent Claudication; Prostaglandins E; Serotonin Antagonists; Sympathectomy; Thromboxane A2

Topics: Adenosine Diphosphate; Animals; Arterial Occlusive Diseases; Epoprostenol; Free Radicals; Photometry; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Strains; Thrombosis; Thromboxane A2; Tranylcypromine; Uric Acid

Topics: Arachidonic Acid; Arachidonic Acids; Arterial Occlusive Diseases; Blood Platelets; Dietary Fats; Humans; Platelet Aggregation; Prostaglandins; Thromboxane A2